[A rare variant in the TTR gene (p.E112K) is associated with systemic amyloidosis and a new symptom - skin hyperemia in response to ethanol intake: family segregation analysis, literature review, and a clinical case. Case report].

Transthyretin amyloidosis (ATTR-amyloidosis) is a systemic disorder associated with extracellular deposition in the tissues and organs of amyloid fibrils, transthyretin-containing insoluble protein-polysaccharide complexes. The change in transthyretin conformation, leading to its destabilization and amyloidogenicity, can be acquired (wild type, ATTRwt) and hereditary due to mutations in the TTR gene (variant, ATTRv) [1, 2]. Hereditary ATTR-amyloidosis has an earlier onset and greater phenotypic diversity. The age of the manifestation, the predominant phenotype, and the prognosis are often determined by the genetic variant. To date, more than 140 variants in the TTR gene have been identified; however, most of them are described in single patients and do not have clear evidence of pathogenicity. The prospects of a new pathogenetic treatment of ATTR-amyloidosis [3], especially effective in the early stages of the disease, increases the relevance of timely diagnosis, which is challenging due to physicians' lack of awareness. This article presents a clinical case of ATTRv-amyloidosis associated with a rare pathogenic variant in the TTR gene and a newly described skin symptom. This article is a literature review.

[The levels of certain circulating microRNAs in hypertrophic cardiomyopathy are associated with echocardiographic parameters].

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease; it is characterized by left ventricular (LV) hypertrophy that cannot be explained by hemodynamic causes. It is believed that sarcomere dysfunction underlies the pathogenesis of this disease, however, only half of patients with the HCM phenotype have mutations in sarcomere-encoding genes. HCM is distinguished by both high genetic and clinical heterogeneity and therefore more studies are seeking to investigate a regulation of gene expression in HCM and how the abnormalities in this process can affect disease phenotype. One of the levels of regulation of gene expression - a post-transcriptional level - is mediated by short non-coding microRNAs that inhibit protein synthesis. AIM: To identify the correlations between levels of circulating microRNAs, previously shown to be associated with HCM, and clinical parameters of HCM patients. MATERIALS AND METHODS: Correlation analysis of miR-499a-5p, miR-454 and miR-339-5p plasma levels and clinical parameters of 33 HCM patients, examined from 2019 to 2021, has been performed. RESULTS: Variants in HCM-associated genes were found in 49% of patients. There were no clinical differences between genotype-positive and genotype-negative patients. MiR-499a-5p level correlated with LV ejection fraction, miR-454 level - with LV diastolic function parameters and miR-339-5p level - with left atrium dimension. CONCLUSION: Levels of certain circulating microRNAs correlate with echocardiographic parameters in HCM patients.

[Molecular cardiology: from decoding the genetic nature and mechanisms of the diseases development to the introduction into the clinic].

In recent decades, advances in molecular biology have led to a change in understanding the inheritance mechanisms and development of cardiological diseases of predominantly genetic origin, such as hypertrophic and dilated cardiomyopathies, familial hypercholesterolemia, etc. This knowledge made it possible to develop fundamentally new drug interventions. Programs for detecting cardiac diseases of predominantly genetic origin have been created, including genetic counseling and testing. Competence in this area is becoming a necessary part of a cardiologist's job.

[Left ventricular global function index as a predictor of adverse cardiovascular events in patients with acute coronary syndrome].

Aim      To evaluate the prognostic significance of the left ventricular global function index (LV GFI) in patients with acute coronary syndrome (ACS) using echocardiography (EchoCG).Material and methods             The LV GFI is an index that integrates LV cavity volumes, stroke volume, and myocardial volume. This study included 2169 patients with ACS (1340 (61.8%) men) aged 64.1±12.6 years from two observational multicenter studies, ORACLE I and ORACLE II. 1800 (83 %) cases were associated with increased concentrations of myocardial injury markers, including 826 (38.1 %) cases of ST segment elevation myocardial infarction (MI). The observation was started on the 10th day of clinical condition stabilization and lasted for one year. EchoCG was performed with evaluation of LV GFI, which was calculated as a ratio of LV stroke volume to LV global volume. The LV global volume was calculated as a sum of mean LV cavity volume (LV end-diastolic volume + LV end-systolic volume / 2) and LV myocardial volume.Results The main outcome of the study was all-cause death (n=193); recurrent coronary complications (n=253) were analyzed separately. The only EchoCG parameter indicating an adverse outcome during the one-year follow-up was a LV GFI decrease to below 22.6 % with a sensitivity of 72 % and a specificity of 60% (area under the curve, AUC=0.63). A LV GFI <22.6 % was an independent predictor of all-cause death (p=0.019) along with age (p=0.0001), history of MI (p=0.034), and presence of heart failure (HF) (p=0.044), diabetes mellitus (p=0.012), and peripheral atherosclerosis (p=0.001). The LV GFI <22.6 %, (p=0.044), heart rate upon discharge from the hospital (p=0.050), history of MI (p=0.006), presence of HF (p=0.014), and peripheral atherosclerosis (p=0.001) were also independent predictors for recurrent coronary complications. Decreased LV GFI was associated with the risk of fatal outcomes independent of the LV ejection fraction at baseline.Conclusion      In patients with ACS, the left ventricular global function index is an independent predictor for all-cause death and recurrent coronary complications and may be used for risk stratification.

[Hypertrophic Cardiomyopathy as an Oligogenic Disease: Transcriptomic Arguments].

Hypertrophic cardiomyopathy (HCM) is the most common genetically determined heart pathology and is often accompanied by fatal complications. Today, the traditional view of the monogenic origin of HCM is being replaced by the idea of it as an oligogenic disease, the clinical phenotype of which is determined not only by mutations in the genes encoding sarcomere proteins in cardiomyocytes, but also by the contribution of other genes (other sarcomeric genes, non-sarcomeric protein-coding modifier genes, and regulatory non-coding RNA genes). Transcriptome analysis is an informative approach for elucidating the nature of HCM, which allows one to evaluate the expression of all genes, evaluate the effect of mutations in a gene on its transcript level, and reveal the mechanisms involved in the regulation of gene expression. This review presents an analysis of published data on the spectra of genes whose differential expression has been detected in the myocardium during the development of HCM in humans and model animals. Special attention is paid to the genes of non-coding regulatory RNAs: miRNAs and long non-coding RNAs, which may be involved in the pathogenesis of the disease. We analyzed studies devoted to the investigation of miRNA levels in the blood of HCM patients to explore the available diagnostic and prognostic biomarkers of the disease. The totality of the reviewed data, despite their relative scarcity, indicates the effectiveness of transcriptome profiling in studying the molecular mechanisms of HCM pathogenesis.

[Left fouratrial heart. First clinical case].

The left three-atrial heart (LTH) is a rare congenital abnormality where the left auricle (LA) is divided into two chambers with an additional membrane. This article describes for the first time a clinical case of congenital heart defect with four atrial chambers. A 41-old man was hospitalized for newly diagnosed paroxysmal atrial fibrillation. On transthoracic echocardiogram (EchoCG), LA was considerably enlarged and divided into two equal interconnected parts with a membrane. Additional examination with contrast-enhanced EchoCG and computed tomography revealed two membranes dividing the LA into three chambers. Prediction for the patient was beneficial since there were no other developmental abnormalities of the heart, and the LA transmembrane pressure gradient (PG) was small. Data of literature on the incidence and prognosis of LTH are provided.

[Hypertrophic cardiomyopathy in elderly: causes, diagnostic and treatment approaches].

Hypertrophic cardiomyopathy is the most common inherited heart disorder with high clinical heterogeneity. Every fifth patient is older than 60 years at first diagnosis. This review discusses the possible causes for the late onset of hypertrophic cardiomyopathy, the diagnostic and treatment approaches in the elderly.

[Early Systolic Dysfunction of Left Ventricular Myocardium Is Reflected On Electrocardiogram of Patients With Aortic Stenosis].

AIM: to study relation between electrocardiographic (ECG) criteria of left ventricular hypertrophy (LVH) and parameters of tissue Doppler (TD) and LV strain in patients with aortic stenosis (AS) with preserved LV ejection fraction. MATERIAL AND METHODS: We examined 80 patients with degenerative AS of all degrees of severity. Examination included history, blood serum cholesterol and creatinine, 12 lead ECG, routine echocardiography (EchoCG), TD, and LV global longitudinal peak strain (GLPS) in apical positions of 2-dimensional EchoCG. RESULTS: ECG criteria demonstrated low sensitivity relative to presence of real LVH. Average values of TD and (GLPS) were lowered in patients with AS. Correlation analysis revealed reverse relationship between TD and GLPX (<0.05). ROC-curve analysis showed very good quality of informativeness of the Cornell index and product for diagnosis of GLPX lowering below - 13%. CONCLUSION: ECG criteria of LVH poorly reflect real LVH but are markers of early systolic LV dysfunction.

[Arterial Hypertension Complicated by Myocardial Hypertrophy and Heart Failure Is Associated With Lower Serum Levels of Vascular Endothelium Growth Factor (VEGF-A165)].

AIM: To study relationships of serum levels of vascular endothelium growth factor with left ventricular (LV) myocardial hypertrophy (H) and signs of heart failure (HF) in patients with arterial hypertension (AH). METHODS: We examined 47 patients with AH and by echo established thickening ( more or equal 16 mm) of LV wall and 47 patients with AH and normal (<12 mm) thickness of LV wall from control group selected according to "head-to-head" principle by age and sex. Serum VEGF-A165 level was measured by sandwich solid-phase immunoenzyme assay. RESULTS: VEGF-A165 level was significantly lower in the group of patients with LVH compared with control group (273.3+/-41.75 vs. 426.6+/-50.00 pg/ml, =0.016). VEGF-A165 level in patients with LVH and NYHA class III HF (140.4+/-51.49 pg/ml) was highly significantly different (p <0.001) from that in in patients without LVH. CONCLUSION: Presence of LVH and HF in patients with AH was associated with lower levels of VEGF-A165 in peripheral blood.

[Degenerative aortic stenosis: prediction of poor prognosis by 2D left ventricular longitudinal strain in non-operated patients].

AIM: To investigate relationship between global longitudinal peak strain (GLPS) of the left ventricle (LV) and clinical routine echocardiographic (ECHO) and electrocardiographic (ECG) parameters in patients with non-operated aortic stenosis (AS) of all degrees. Also we evaluated the prognostic value of GLPS in patients with AS. METHODS: Patients with AS (n = 80) and control patients (n = 49) matched by age, sex and main cardio-vascular diseases were examined. Examination included medical history, serum cholesterol and creatinine, ECG, routine ECHO, tissue Doppler imaging (TDI), and GLPS in apical views. Correlation analysis and unifactorial regression analysis for assessment of one year prognosis were performed in AS group. RESULTS: Average GLPS (GLPS_Avg) for whole LV was significant lower in AS group than in control group (-17.4 +/- 3.85 vs -19.3 +/- 3.99, p < 0.05). In AS group GLPS_Avg correlated with aortic valve area (r = 0.318, p = 0.004), LV ejection fraction (r = 0,305, p = 0,006), thickness of interventricular wall (r = -0.246, p = 0.028), QRS duration (r = -0.225, p = 0.045), and Cornell (r = -0.338, p = 0.003) and Gubner (r = -0.281, p = 0.013) ECG hypertrophy indexes. The GLPS_Avg below -13% was associated with risk of unfavorable one-year outcome in patients with AS. CONCLUSION: . GLPS for the whole LV correlated with early ECG and ECHO parameters of LV hypertrophy. GLPS has prognostic value for one-year outcomes in patients with degenerative non-operated AS.

[The pulse wave velocity and fatal events rate in hypertensive patients have gone through acute coronary syndrome].

There are several stratification scales of major cardiovascular events rate for patients have gone through acute coronary syndrome (ACS). None of them is perfect one. Arterial hypertension is included into some scales for post ACS patients but the features of it and its impact on coronary artery disease after ACS have never studied before. We studied the reasonability of Pulse Wave Velocity (PWV) measurement for fatal events rate in hypertensive patients have gone through ACS. 326 patients were examined. They were enrolled into the study in stable condition on 10th day after ACS has occurred. As a result of two years observation the increase PWV on carotid-femoral segment associated with the most negative (fatal) events in hypertensive patients have gone through ACS.

[Cystatin C level is independently related to risk of unfavorable outcome after acute coronary syndrome in individuals with normal or moderately reduced renal function].

We studied relation between cystatin C level and risk of unfavorable outcome (unstable angina, fatal and nonfatal myocardial infarction [MI], fatal and nonfatal stroke, and death) in patients stabilized after exacerbation of ischemic heart disease. Patients (n=272) were included on day 10 after onset of acute coronary syndrome. No relationship between studied outcomes and cystatin was found in a group as a whole. In patients with normal of slightly reduced renal function (glomerular filtration rate more or equal 60 ml/min/1.73 m2) unfavorable outcomes were independently associated with history of myocardial infarction and stroke, elevated levels of brain natriuretic peptide and cystatin. In subjects with moderately or severely reduced renal function elevation of cystatin level lost its significance. Risk of development of unfavorable outcomes among these subjects was independently related to history of MI and GFR <60 ml/min/1.73 m2 (OR 2.130, 95% CI 1.010-4,489; =0,047). Our data confirm possibility of use of cystatin C level measured early after ACS in patients with normal or slightly lowered renal function as a parameter characterizing risk of cardiovascular complications and death.

[Prognostic value of levels of brain natriuretic peptide and genetic factors in patients after acute coronary syndrome].

Prognostication of the course of disease in patients with high risk of unfavorable outcome of ischemic heart disease (IHD) is of great importance for creation of individualized strategy of treatment. We have investigated contribution of levels of brain natriuretic peptide (BNP) and genetic factors in the risk of development of complications of atherosclerosis in patients who have had acute coronary syndrome. We started to follow 324 patients on day 10 of stable state after acute coronary syndrome (55.1% with Q-wave myocardial infarction, 18.5% with non-Q myocardial infarction, 25.5% with unstable angina, men BNP level 624.5+/-32.13 mol/ml [70.3 - 4276.6]). Duration of followup was 2 years. Baseline BNP level in patients with unfavorable outcome during followup (fatal and nonfatal myocardial infarction and stroke) was 872.47+/-91.42 compared with 592.45+/-35.97 mol/ml in patients without unfavorable outcome (p=0,001). Multifactorial Cox analysis showed that carriage of T allele of polymorphic marker (--1654) of protein C gene, elevated BNP level, symptomatic atherosclerosis of peripheral arteries, history of MI, and use of thiazide diuretics were independently associated with unfavorable outcomes (p=0.026, <0.0001, <0.0001, =0.001, =0.024, respectively). Thus genetic factors and study of BNP allow to improve prediction of unfavorable outcome after exacerbation of IHD.

[Prognostic value of aortic stenosis in patients after acute coronary syndrome].

With the aim to assess prevalence of aortic stenosis (AS) and prognostic value of its detection among survivors of acute coronary syndrome (ACS) we examined 851 patients included into multicenter prospective study of risk factors of serious vascular events and death after acute coronary syndrome. The patients were enrolled into the study in stable condition on 10th day after onset of myocardial infarction (MI) or unstable angina (UA). Examination involved medical history, laboratory tests and echocardiography. Afterwards all cases of death and serious vascular events were registered. Severity of AS was specified by maximal aortic flow rate: 1st degree > 2.5, 2nd degree 3.0-4.0, 3rd degree > 4.0 m/s. AS was detected in 16 patients (1.9%). AS severity was 1st, 2nd and 3rd degree in 9, 4 and 3 patients, respectively. Patients with AS were significantly older (77.4 vs. 61.3 years, p < 0.001), more often had history of chronic heart failure (CHF) (81.3 vs. 53.2%, p = 0.021) and lowered renal function (66.7 vs. 34.0%, p < 0.041). At multifactorial analysis independent prognostic value in relation to development of serious events showed age > 75 years (OR 1,395 [1.023-1.902], p = 0.036), history of CHF (1.319 [1.015-1.713], p = 0.038), history of MI (1.692 [1.320-2.170], p < 0.001), left ventricular diastolic dimention (1.023 [1.005-1.041], p = 0.012), left atrial diameter (1.024 [1.001-1.047], p = 0.037) and presence of AS (3.211 [1.742-.,916], p < 0.001). Prevalence of preexisting AS among patients who have had MI/UA is 1.9% what is similar to data of European Heart Survey ACS-II (1.8%). Presence of AS of any severity in a survivor of ACS worsens prognosis independently of other known risk factors.

[Polymorphic markers G(-455)A of gene FGB and C(-1654)T of gene PROC and genetic predisposition to unfavorable outcomes patients undergoing acute coronary syndrome].

We investigated the association of polymorphisms of genes FGB G(-455)A and PROCC(-1654)T with coronary artery disease (CAD) in the Russian population. A total of 1145 patients with CAD diagnose on the basis of clinical studies in cardiological hospitals of Moscow, St. Petersburg, Kazan, Chelyabinsk, Perm, Stavropol and Rostov-on-Don. Supervision term was 1.14 +/- +/- 0.33 years (the maximum term 3.2 years). The group studied do not differ significantly with respect to the distributions of G(-455)A alleles and genotypes. However in case of gene PROC C(-1654)T polymorphism we determined that patients with CAD diagnose and Talleles of PROC gene had unfavorable outcome more often than patients with homozygous C alleles. Survival time from end point from carrier phenotype TT and CTis 2.19 +/- 0.18 r. years against 2.46 +/- 0.16 from carrier phenotype CCgene PROC. The obtained data allows to assume the important role of the genes which are responsible for functioning of system of a hemostasis, in the accelerated formation of failures at the patients who had a coronary syndrome.

[Gene IL6 G(-174)C and gene IL10 G(-1082)A polymorphisms are associated with unfavourable outcomes in patients with acute coronary syndrome].

We investigated the association of gene IL6 G(-174)C polymorphism and gene IL10 G(-1082)A polymorphism with coronary artery disease (CAD) in the Russian population. A total of 1145 patients with CAD diagnose on the basis of clinical studies in cardiological hospitals of Moscow, St -Petersburg, Kazan, Chelyabinsk, Perm, Stavropol and Rostov-on-Don. Supervision term was 9.10 +/- 5.03 months (the maximum term 18 months). In case of gene IL10 G(-1082)A polymorphism we determined that patients with CAD diagnose and A alleles gene IL10 had unfavorable outcome more often than patients with homozygous G alleles. Survival time from end point from carrier genotype GA and AA is 11.68 +/- 0.67 months against 12.69 +/- 0.65 months from carrier phenotype GG gene IL10 (chi2 = 4.13, p = 0.042). The group studied do not differ significantly with respect to the distributions of gene IL6 G(-174)C alleles and genotypes. However in case combined group studies of gene IL10 G(-1082)A polymorphism and IL6 G(-174)C polymorphism we determined that patients with CAD diagnose and carrier genotype GG gene IL6 and genotype GA and AA gene IL10 had unfavorable outcome more often (survival time 11.01 +/- 1.24 months) than patients with genotype CC and CG gene IL6 and genotype GG gene IL10 (survival time 13.28 +/- 0.83 months) chi2 = 10.23, p = 0.017. The obtained data allows assuming the important role of the IL6 and IL10 genes which are responsible for functioning of inflammation system, in the accelerated formation of failures at the patients who had a coronary syndrome.

[Effect of twelve-month combined therapy with perindopril and indapamide on the level of blood pressure and left ventricular hypertrophy in patients with hypertensive disease].

Left ventricular hypertrophy (LVH) in patients with hypertensive disease is associated with unfavorable prognosis. Long term and effective antihypertensive therapy is capable to cause reverse development of LVH. We included in this study 72 patients (27 men, 45 women, age from 34 to 72 years) with untreated 1st and 2nd degree arterial hypertension (systolic blood pressure 140-179 mm Hg and/or diastolic blood pressure 99-109 mm Hg) and echocardiographical signs of LVH (left ventricular myocardial mass index >120 g/m2 in men and >100 g/m2 in women). After that the patients were randomized into 2 groups: the study group (39 patients, mean age 53.0+/-11.6 years) received combination of perindopril and indapamide in initial dose of 2 mg/0.625 mg, and comparison group (33 patients, mean age 54.4+/-8.2 years) received monotherapy with enalapril (10 mg). Once daily dosing of the preparation provided high level of compliance of patients with treatment. During 12-month therapy with combination of perindopril and indapamide target blood pressure (<140/90) was achieved in 74.4% of patients, during monotherapy with enalapril--in 27.3% of patients. Significant decrease of left ventricular myocardial mass index (LVMMI) with combination therapy was observed by 6th month of treatment (from 260 to 234 g), with monotherapy within same period of time--from 267 to 260 g. As a result of 12 months therapy of patients with I-II degree of hypertension with perindopril and indapamide LVMMI decreased by 17.5% while monotherapy with enalapril was associated with 5.6% decrease of LVMMI. Lowering of LVMMI occurred mainly at the account of decrease of left ventricular wall thickness.

[Genetic Predictors of Unfavorable Course in High Risk Patients With Ischemic Heart Disease. Data of Follow-up for Two Years.]. / Geneticheskie prediktory neblagopriiatnogo techeniia zabolevaniia u bol'nykh ishemicheskoi bolezn'iu serdtsa vysokogo riska po dannym 2-letnego nabliudeniia.

Prognostic value of clinical parameters and polymorphisms of apo-B, apo-E, LPL, , PPARA, PPARG2 genes was studied in 154 patients with acute unstable angina. Duration of follow-up was 2 years. Diabetes (OR 3.29, 1.28-8.50, p=0.014), history of stroke (OR 6.11, 1.21-31.00, p=0.029), changes of terminal part of ventricular complex on ECG, recorded during acute phase of ischemic heart disease (OR 2.19, 1.01-4.57, p=0.046), and genotype II of polymorphic marker ID of apoB gene (OR 2.20, 1.06-4.57, p=0.027) were independent predictors of unfavorable course of ischemic heart disease. Thus genetic factors play a role not only in formation of coronary atherosclerosis but determine the course of ischemic heart disease.